AT376423B - METHOD FOR PRODUCING NEW 1,2,4TRIAZOLE DERIVATIVES - Google Patents

Description

  

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   The invention relates to a process for the preparation of new 1, 2, 4-triazole derivatives with an activity on histamine receptors, which are accordingly used in therapy.



   According to the invention, certain new 1, 2, 4-triazole derivatives have been found which have strong activity as H2-antagonists. These compounds, which will be described in detail later, show, for example, an inhibition of gastric acid secretion when stimulated by histamine receptors (Ash and Schild, Brit. J. Pharmcol. Chemother., 1966, 27,427).



  Their ability for this can be determined using the method described in DE-US 2734070 in the soaked rat stomach, which method was modified by using sodium pentobarbitone (50 mg / kg) as an anesthetic instead of urethane, and using the method described by Black et al . method described in Nature 1972, 236, 385, in conscious dogs which are provided with Heidenhain bags. Furthermore, the compounds counteract the effect of histamine on the contraction frequency of the isolated right auricle of guinea pigs, modified but not histamine-induced contractions of isolated smooth muscles of the gastrointestinal tract, which are mediated via receptors.

   Certain compounds obtainable according to the invention have the advantage that they have a long duration of action.



   Compounds with histamine Hs blocking activity can be used in the treatment of conditions where gastric acid over-secretion is present, particularly gastric ulcers, as a prophylactic measure in surgery and in the treatment of allergic and inflammatory conditions where histamine is a known mediator . For example, they can be used either alone or in combination with other active ingredients in the treatment of allergic and inflammatory conditions of the skin.



   The invention thus relates to a process for the preparation of new 1, 2, 4-triazole derivatives of the general formula
 EMI1.1
 wherein R 1 and R 2 are the same or different and each represents hydrogen, C 1-10 alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, trifluoroalkyl or alkyl, substituted by hydroxy, alkoxy, amino, alkylamino, dialkylamino or cycloalkyl, or R, and R 2 together with the nitrogen atom to which they are attached form a 5- to 10-membered alicyclic heterocyclic ring which may be saturated or contain at least one double bond, unsubstituted or optionally by one or more C 1-3 alkyl groups, such as methyl, or a hydroxy group is substituted and / or a further heteroatom,

   such as oxygen or sulfur; Alk is straight or branched alkylene with 1 to 6 C atoms, preferably 1 to 4 C atoms;
 EMI1.2
 
 EMI1.3
 
 EMI1.4
 
 EMI1.5
 
 EMI1.6
 Represents alkoxyalkyl or aryl; and R., and Rs are identical or different and each represent hydrogen, alkyl, hydroxy- or C -allcoxy-substituted alkyl, alkenyl, aralkyl or pyridylalkyl, where the pyridyl part can be substituted by one or more C 1 -C 6 -alkyl groups

  <Desc / Clms Page number 2>

 or R4 and Rs together with the nitrogen atom to which they are attached, a 5- to 7-membered saturated heterocyclic ring which is another heteroatom, such as oxygen, or the
 EMI2.1
 
 EMI2.2
 
 EMI2.3
 
 EMI2.4
 Group is straight or branched and,

   unless otherwise stated, preferably has 1 to 6 carbon atoms, in particular 1 to 4 carbon atoms, z. B. methyl or ethyl. The terms "alkenyl" and "alkynyl" refer to groups with preferably 3 to 6 carbon atoms. The term "cycloalkyl" denotes a group with 3 to 8 carbon atoms. The term "aryl" as a group or part of a group preferably means phenyl or substituted phenyl, e.g.

   B. phenyl one or
 EMI2.5
 prepared physiologically usable salts and hydrates, wherein R, and R2 are identical or different and each is hydrogen, Cl, alkyl, cycloalkyl, C3 6-alkenyl, aralkyl or Cl 6-alkyl, substituted by alkoxy, alkylamino or dialkylamino or R i and R 2 together with the nitrogen atom to which they are attached form a 5- to 10-membered alicyclic heterocyclic ring which may contain oxygen; Alk is straight or branched alkylene with 1 to 6 C atoms;

   Q represents a furan or thiophene ring, the incorporation into the rest of the molecule via bonds in positions 2 and 5, the furan ring optionally carrying a further substituent R7, which is adjacent to the group RRN-Alk, or Q being a benzene ring , which is incorporated into the rest of the molecule via bonds in positions 1 and 3; R7 represents Cl-4 alkyl optionally substituted by hydroxy or Cl-4 alkoxy; X is -CH2-, -0- or -S-; n is zero, 1 or 2 and m is 2, 3 or 4;

   Ra represents hydrogen, Cl 6-alkyl, C3 6-alkenyl, hydroxyalkyl with at least 2 C atoms, alkoxyalkyl, aryl or aralkyl; and R and R 5 are the same or different and each represents hydrogen or Cl 6 alkyl; with the proviso that n cannot be zero if Q is a furan, substituted furan or thiophene ring system and X is oxygen.



   The invention comprises the preparation of compounds of formula (I) in the form of physiologically usable salts with inorganic and organic acids. Particularly useful salts are hydrochlorides, hydrobromides and sulfates; Acetates, maleates, succinates, citrates and fumarates. The compounds of formula (I) and their salts can also form hydrates, which hydrates also fall within the scope of the invention. The compounds of formula (1) can exhibit tautomerism and the formula is intended to encompass all tautomers. If optical isomers can exist, the formula should include all diastereoisomers and optical enantiomers.



   The compounds obtainable according to the invention, preferably in the form of salts, can be formulated for administration in any manner. Accordingly, they are used for the production of pharmaceutical compositions which contain at least one compound obtainable according to the invention as an active ingredient for use in human or veterinary medicine. Such compositions can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers or excipients. Such compositions can also, if necessary, other active ingredients, e.g. B. HF antagonists.



   The compounds obtainable according to the invention can thus be formulated for oral, buccal, topical, parenteral or rectal administration. Oral administration is preferred.



   For oral administration, the compositions can be formulated, for example, in the form of tablets, capsules, powders, solutions, syrups or suspensions which have been prepared in a conventional manner with acceptable excipients. For buccal administration, the

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 composition in the form of tablets or lozenges, which have been formulated in a conventional manner.



   The compounds obtainable according to the invention can be formulated for parenteral administration by bolus injection or by continuous infusion. Formulations for injections can be prepared in unit dose form in ampoules or in multiple dose containers with the addition of a preservative. The compositions can be present as suspensions, solutions or emulsions in oily or aqueous vehicles and contain formulation additives such as suspending, stabilizing and / or dispersing agents. On the other hand, the active ingredient can be reconstituted with a suitable carrier, e.g. B. sterile pyrogen-free water, before use in powder form.



   The compounds obtainable according to the invention can also be formulated into rectal compositions, such as suppositories or retention enemas, for example containing conventional suppository bases, such as cocoa butter or another glyceride.



   For topical use, the compounds obtainable according to the invention can be formulated as ointments, creams, gels, lotions, powders or sprays. For example, ointments and creams can be formulated with an aqueous or oily base with the addition of suitable pharmaceutical excipients. Lotions can be formulated with an aqueous or oily base and include the necessary settings to ensure pharmaceutically acceptable products. Spray compositions can be formulated, for example, as aerosols that can be pressurized using a suitable agent, such as dichlorofluoromethane or trichlorofluoromethane, or can be dispensed using a hand-operated atomizer.



   For internal administration there is a convenient daily dosing system for the compounds obtained according to the invention in 1 to 6 doses up to a total amount of 5 mg to 2 g / day, preferably 5 to 500 mg / day.



   In the compounds obtainable according to the invention, the total number of m + n is 3 or 4, in particular 3.



   If X is sulfur, n is preferably 1 and m is preferably 2. If X is oxygen or
 EMI3.1
 
 EMI3.2
 of the molecule is incorporated through bonds in positions 1 and 3 or 1 and 4.



   Alk is preferably methylene, ethylene or propylene.
 EMI3.3
 if contains a double bond and / or is substituted by hydroxy or one or two Cl-3-alkyl groups.



   R is preferably hydrogen or Cl-4 alkyl or hydroxyalkyl.



   Preferably R 4 is hydrogen or C1 s-alkyl, optionally substituted by phenyl, pyridyl, hydroxy or C1 3-alkoxy, and R 5 is hydrogen or Cl 3-alkyl or R4 and Rs form with the nitrogen atom to which they are attached, a C5-7 saturated heterocyclic ring or the group = CHRe, where R is phenyl or pyridyl.



   If R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocyclic ring, this ring can pyrrolidine, piperidine, optionally substituted in position 4 by Cl 3-alkyl or hydroxy, tetrahydropyridine, morpholine, 2, 6-dialkylmorpholine, Be hexamethyleneimine or heptamethyleneimine.



   When Q represents a furan or substituted furan ring, alk is preferably methylene,
 EMI3.4
 

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 a substituted furan group, in which R7 is Cl 3-alkyl, in particular methyl, which is optionally substituted by Cl 3-alkoxy, in particular methoxy.



   When Q represents a benzene ring, alk is preferably methylene, ethylene or propylene; n is zero; X is oxygen or NH; m is 3 or 4; R1 is hydrogen or C1-4 alkyl; R2 is
 EMI4.1
 
Cl 7 alkyl group, see heterocyclic ring which may be saturated or may contain at least one double bond or may be saturated and one or more times by C, -alkyl, e.g. B. methyl, may be substituted and another heteroatom, for. B. may contain oxygen; R3 is hydrogen or Cl 2 alkyl
 EMI4.2
 and R2 C1-7 alkyl, e.g. Methyl, propyl, butyl, sec. Butyl and n-heptyl, or C3-5 alkenyl, e.g. Allyl, or - --cycloalkyl, e.g.

   B. cyclohexyl, or form R1 and R2 together with the nitrogen atom to which they are attached, a 5- to 7-membered alicyclic heterocyclic ring, which may be saturated or contains or contains a double bond and saturated by a Cl 3 alkyl group, for . B. methyl, may be substituted, especially pyrrolidine, piperidine optionally substituted in position 4 with methyl, or tetrahydropyridine or hexamethyleneimine; and R3 is hydrogen, methyl, ethyl or hydroxyethyl; R and Rs are both hydrogen or ethyl or R4 and R5 together form the group = CHR, where R is phenyl or 4-pyridyl.

   Particularly preferred compounds in which Q is benzene are those in which this is incorporated into the rest of the molecule through bonds in positions 1 and 3 and in which alk is methylene, n is zero, X is oxygen and m 3.



   Particularly preferred compounds obtainable according to the invention are those in which R3 is methyl and R i. and Rs each represent hydrogen.



   Particularly preferred compounds are:
1. 1-Methyl-N {3- [3- (1-piperidinylmethyl) phenoxy] propyl} -1H-1,2,4-triazole-3,5-diamine
 EMI4.3
 

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 17. 1-Methyl-N {3- [3- (1- [4-methylpiperidinyl] methyl) phenyoxy] propyl} -1H-1,2,4-triazole- - 3,5-diamine 18. 1 -Methyl-N5- {3- [3 - ([cyclohexylamino] methyl) phenoxy] propyl} -1H-1,2,4-triazole-3,5-diamine 19. 1-Methyl-N5- {3- [3 - ([2-propen-1-amino] methyl) phenoxy] propyl} -1H-1,2,4-triazole-3,5-diamine 20. 1-methyl-N '- {3- [3 - ([heptylamino] methyl) phenoxyl] propyl} -1H-1,2,4-triazole-3,5-diamine 21. 1-Methyl-N5- {3- [3rd - ([2-methylpropylamino] methyl) phenoxy] propyl} -1H-1,2,4-triazole -3,5-diamine
 EMI5.1
 {3- [3- ([2, 2, 2-trifluoroethylamino] methyl) phenoxy] propyl} -lH-1,2,4-triazole-- 3,5-diamine
25th

   1- (2H-Hydroxyethyl) -N5- {3- [3 - ([1-piperidinylmethyl] phenoxy)] - propyl} -1H-1,2,4-triazole- - 3, 5-diamine and their physiologically acceptable Salts.



   Of the above-mentioned compounds, compounds 1, 2, 3 and 4 and their salts are particularly preferred.



   The process according to the invention is characterized in that for the preparation of compounds in which R4 and Rs have a meaning other than = CRoR. have a compound of the general formula
 EMI5.2
 wherein Q, n, X, m and Rs have the meaning given in formula (I) and in which at least one of the groups D, D 'and D' 'is one of the following reducible groups, and the other (n) is that in formula ( I) has the meaning given;
 EMI5.3
    Rz is NAlk, D''NR4Rs, where R., and R s have the meaning given in formula (I) or -NR.

   COR 11 represents in which R4 has the meaning given in formula (I) and Ru is hydrogen, alkyl, optionally substituted by hydroxy, aryl, aralkyl or alkoxy, whereupon, if appropriate, for the preparation of compounds in which R4 and Rs are together the group = CR. Form R9, a compound of formula (I), wherein R4 and R s are both hydrogen, with the aldehyde
 EMI5.4
 and / or a compound (I) obtained is converted into a salt.



   For example, compounds of formula (I) in which R4 and Rs have a meaning other than = CR R9 can be obtained by reducing compounds of the general formula
 EMI5.5
 

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 EMI6.1
 mel (I) have the meaning given and p is zero, 1, 2, 3, 4 or 5. Compounds of formula (I) wherein Alk is CH2 can be prepared from compound (III) where W is CHO by reaction with ammonia or an amine R, R2NH in a solvent, e.g. B. tetrahydro
 EMI6.2
 tion can be carried out with aluminum hydride or lithium aluminum hydride in a suitable solvent, such as dioxane or tetrahydrofuran.

   The compounds of the formula (III) can be obtained from an amine of the general formula
W-Q- (CH2) nX (CH2) n -NH2 (IV) where W is R1R2NCO (CH2) n or a protected aldehyde group, e.g. B. an acetal or cyclic ketal, in an analogous manner as described for the preparation of the corresponding compounds of formula (I).



   According to another aspect of the reduction of the compounds of the formula (II), compounds of the formula (I) in which R4 and Rs have a meaning other than = CR, R, can be obtained by reducing an amide of the general formula
 EMI6.3
 
 EMI6.4
 with a suitable reducing agent, such as lithium aluminum hydride or an aluminum hydride, in a solvent, such as tetrahydrofuran or dioxane, at temperatures from ambient temperature to reflux temperature.



   Compounds of formula (V) in which Ra is hydrogen and R4 and Rs are both hydrogen or alkyl or in which Ra has a meaning other than hydrogen and R4 and Rs both represent alkyl can be obtained from an activated derivative of a carboxylic acid of the general formula
 EMI6.5
 and the appropriate diaminotriazole of the general formula
 EMI6.6
 wherein Ra is hydrogen and R4 and Rs. are both hydrogen or alkyl, or wherein Ra has a meaning other than hydrogen and R4 and R: both are alkyl.



  Suitable activated acid derivatives are acyl halides, mixed acid anhydrides, esters, e.g. B.



    Alkylestel'or (1-alkyl-2-pyridinyl) esters and products formed by reacting the carboxylic acid with a coupling agent such as carbonyldiimidazole or a carbodiimide such as dicyclohexylcarbodiimide.



   The diaminotriazole (VII), wherein R4 and R s both have a meaning other than hydrogen

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 can by reacting a compound R4RsNCO. Hal, where Hal is halogen, with the aminoguanidine of the general formula
 EMI7.1
 in a solvent such as benzene or acetonitrile.



   According to a further aspect of the reduction of compounds of the formula (II), compounds of the formula (I) in which R 4 and R 5 have a meaning other than = CRBR9 can also be reduced by reducing an imine of the general formula
 EMI7.2
 wherein Ri, R:, Alk, Q, n, X, m, Rg, R4 and R 5 have the meaning given in formula (I). Suitable reducing agents are metal hydrides, such as alkali or alkaline earth metal
 EMI7.3
 Tetrahydrofuran or dioxane. The imine (IX) can also be hydrogen or a suitable metal catalyst such as platinum in a solvent such as an alkanol, e.g. As methanol or ethanol can be reduced.



   The imine (IX) can be obtained by reacting an aldehyde of the general formula
 EMI7.4
 with the diaminotriazole (VII) in a suitable solvent such as benzene, toluene, ethanol or methanol, preferably with heating, optionally in the presence of an acid catalyst, e.g. As hydrochloric acid or p-toluenesulfonic acid are formed.



   In the above process, it is sometimes unnecessary to isolate the imine (IX). For example, treating a mixture of an aldehyde (X) and a triazole (VII) in one
 EMI7.5
 expediently with an alkali or alkaline earth metal borohydride, such as sodium borohydride, or with hydrogen and a metal catalyst, such as platinum or palladium. Similarly, compounds of formula (I) wherein R4 and Rs are both alkenyl or alkyl, optionally substituted with hydroxy, by reacting a compound of formula (I) wherein at least one of R4 and R5 is hydrogen with the appropriate aldehyde or Ketone and subsequent reduction can be prepared by the method described above.



   According to a further embodiment of the reduction process described above, compounds of the formula (I) in which R 1 and / or R 5 have a meaning other than hydrogen,
 EMI7.6
 or RasCH2 are reducible, the latter having the meaning of Ri or Rs.



   The reduction is preferably carried out with aluminum hydride or lithium aluminum hydride in a solvent such as dioxane or tetrahydrofuran.

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   The compounds of the formula (II) in which D and / or D "have the meanings RCONR2Alk or - COR Sa can be obtained by treating a compound of the formula (I) in which R1 and / or
 EMI8.1
 getting produced.



   Compounds of formula (I), wherein R, and Rs together the group = CReRR. can, as mentioned, be prepared from compounds of formula (I), wherein R4 and Rs are both hydrogen, by reaction with an aldehyde or ketone RRaCO in a solvent such as benzene, ethanol or methanol. The reaction is preferably carried out with heating, e.g. B. performed at reflux.



   The compounds of the formulas (IV) and (VI) can be prepared in accordance with DE-OS 2734070,2821400 and 2821409 or in an analogous manner to that described in these DE-OS. The aldehydes of the formula (X) can be obtained by partial reduction of acids of the formula (VI).



   If the product of one of the above processes is a free base and a salt is desired, the salt can be formed in a conventional manner. For example, a commonly used method for forming the salts is to add suitable amounts of the free base or acids in a suitable solvent (s), e.g. B. an alcohol, such as ethanol, or an ester, such as ethyl acetate.



   The following examples or preparations are intended to explain the process according to the invention for the preparation of compounds of the formula (I) or the preparation of starting materials which can be used in processes according to the invention.



   Manufacturing 1; N-cyano-1-methyl-2- (phenylmethylene) hydrazine carboximidothioic acid ethyl ester
A mixture of 1.46 g of dimethyl cyanocarbonimidodithioate and 1.34 g of benzaldehyde-N-methylhydrazone in acetonitrile was refluxed for 50 hours. The reaction
 EMI8.2
 



   Thin layer chromatography (TLC), silica gel, 0.25 mm thick / ethyl acetate: petroleum ether (bp.



  60 to 80 C) 1: 4, a spot Rf 0.35.



   Similarly, 3 g of benzaldehyde-N-ethylhydrazone and 1.46 g of cyanocarbonimidodithionic acid dimethyl ester gave 2.1 g of N-cyano-l-ethyl-2-phenylmethylene) -hydrazinecarboximidothio-
 EMI8.3
 Using a Dean-Stark trap heated to reflux. The cooled solution was washed successively with sodium carbonate solution, water and sodium chloride solution and evaporated in vacuo. The oil obtained was dissolved in 1 liter of tetrahydrofuran and stirred with 50 ml of hydrazine hydrate for 24 hours at room temperature. The mixture was diluted with ether and filtered.



  The filtrate was distilled to give 55.2 g of the compound mentioned in the title as a colorless oil, bp 134-136 C (93.1 Pa). TLC silica; Methanol-ammonia 80: 1; Rf 0.4.
 EMI8.4
 Toluene was stirred at room temperature for 4 hours. The white precipitate was filtered off and the filtrate was distilled to give 17.56 g of the compound mentioned in the title as a colorless oil, bp 110 C (13.3 Pa), TLC silica; Ether; Rf 0.7.



   3- (1-piperidinylmethyl) benzene methanol
A mixture of 17.56 g of methyl 3- (1-piperidinylmethyl) benzoate and 2.68 g of lithium

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 aluminum hydride in 500 ml of tetrahydrofuran was stirred at room temperature for 30 hours and cooled with water. The solid was filtered off and the filtrate was distilled to give 11.1 g of the compound mentioned in the title as a colorless oil, bp. 135 C (13.3 Pa). TLC silica; Ether; Rf 0.2.



    2- [{[3- (l-piperidinylmethyl) phenyl] methyl} thio] ethanolamine
A mixture of 10, 8 g of 3- (1-piperidinylmethyl) benzene methanol and 6.48 g of cysteamine hydrochloride in 25 ml of conc. Hydrochloric acid was heated to 100 ° C for 3 hours. The cooled mixture was added to 500 ml of ether and treated with an excess of sodium carbonate. The organic solution was filtered and distilled to give 9.51 g of the title compound as an oil, bp 1750C (8 Pa). TLC silica; Ethyl acetate-water: isopropanol: 0.88 ammonia 25: 8: 15: 2; Rf 0.7.



   Preparation 4: 2- [3- {4- [2- (dimethylamino) ethyl] phenoxy} propyl] 1H isoindole-l, 3- (2H) dione
A mixture of 4.13 g of 4- [2- (dimethylamino) ethyl] phenol and 0.77 g of sodium hydride in dimethylformamide was stirred at room temperature for 24 hours. 6.7 g of N- (3-bromopropyl) phthalimide were added at 0 ° C. and stirring was continued for 24 hours. The solution was treated with water and extracted with ether. When the solvent was evaporated, 2.3 g of the compound mentioned in the title were obtained as a white solid which was recrystallized from petroleum ether (bp. 60 to 80 ° C.); Mp 81-82 C. TLC silica; Ethyl acetate: water: isopropanol: 0.88 ammonia 25: 8: 15: 2; Rf 0.45.



   Similarly, 7.2 g of 4- [[3- (dimethylamino) propyl] phenol, 1.06 g of sodium hydride and 10.7 g of N- (3-bromopropyl) phthalimide became 5.2 g of 2- [ 3- (4- [3-dimethylamino) propyl] phenoxy} propyl] -1H-isoindole-1,3- (2H) -dione obtained, mp. 67 to 67.5 C. TLC silica; Ethyl-
 EMI9.1
    882.1 g of 2- [3- {4- [2- (dimethylamino) ethyl] phenoxy} propyl] -1H-isoindole-1,3- (2H) -dione and 1.2 ml of hydrazine hydrate were added for 4 hours long refluxed in ethanol. The solvent was evaporated and the residue was distilled to give the compound mentioned in the title as a clear yellow oil, bp 170 C (13.3 Pa). TKC silica, ethyl acetate / water / isopropanol / 0.88 ammonia 25: 8: 15: 2. Rf 0.35.



   Similarly, 4.4 g of 2- [3- {4- [3- (dimethlamino) propyl] phenoxy} propyl] -1H-iso-
 EMI9.2
 
50 g of 2- [3- (formylphenoxy) propyl] -1H-isoindole-1,3-dione and 20.7 g of piperidine in 750 ml of ethyl acetate were hydrogenated over 10% palladium / carbon catalyst. The catalyst was filtered off and the solvent was evaporated; then 40 ml of hydrazine hydrate was added to an ethanolic solution of the residue at 25 ° C. After 67 hours, the reaction mixture was diluted with ether and filtered, and the filtrate was distilled, giving 31.05 g of the compound mentioned in the title as a colorless oil, bp. 154 to 1580C (19.95 Pa). TLC silica; Methanol / 0.88 ammonia 80: 1; Rf 0.2.



   The following compounds were prepared in a similar manner from the appropriate phthalimide A and the corresponding amine: (ii) 50 g of A and 25 g of hexamethyleneimine gave 19.4 g of 3- [3- (I-hexamethyleneiminylmethyl) - - phenoxyj-propanamine, bp 170 to 1740C (33, 25 Pa). TLC silica; Methanol / 0.88
Ammonia 80: 1; Rf 0.2.



   (iii) 5 g of A and 3.21 g of 2,2,2-trifluoroethylamine gave 1.5 g of 3- (3-aminopropoxy) -N- - (2,2,2-trifluoroethyl) -benzenemethanamine, b.p. 130 C. / 13, 3 Pa. TLC silica; Ethyl acetate / water / isopropanol / 0.88 ammonia 25: 8: 15: 2; Rf 0.57.



   (iv) 25 g of A and 20 ml of N-methylbutylamine gave 1.84 g of 3- (3-aminopropoxy) -N-butyl-N- - methylbenzenemethanamine, b.p. 135 C / 13, 3 Pa. TLC silica; Ethyl acetate / water / isopropanol / 0.88 ammonia 25: 8: 15: 2; Rf 0.36.

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 EMI10.1
 
Preparation 6: 3- (1-piperidinylmethyl) phenol
15 g of 3-hydroxybenzaldehyde and 15 ml of piperidine in 500 ml of ethanol were hydrogenated over 10% palladium / carbon catalyst. The catalyst was filtered off and the solvent was evaporated.

   The residue was triturated with petroleum ether (b.p. 60 to 80 ° C.) and the solid obtained was recrystallized from acetonitrile, giving 8.7 g of the compound mentioned in the title as a brown solid, mp. 134 to 137 C. TLC silica; Methanol; Rf 0, 56.



   4- [3 - (l-piperidinylmethyl) phenoxy] butane amine
A mixture of 8.7 g of 3- (I-piperidinylmethy1) phenol and 1.2 g of sodium hydride in 60 ml of dimethylformamide was stirred at 25 ° C. for 3 hours. 12.8 g of N- (4-bromobutyl) phthalimide were added and the mixture was stirred at 25 C for 20 h and then at 65 C for 3 h. The reaction mixture was poured onto water and extracted with ethyl acetate. The solvent was concentrated and the crystalline impurity was filtered off. The filtrate was evaporated in vacuo and the residue was dissolved in ethanol and heated under reflux with 2.5 ml of hydrazine hydrate for 3 hours.



  The mixture was filtered and the filtrate was distilled to give 4.1 g of the compound mentioned in the title as a colorless oil, bp 140 C / 13.3 Pa. TLC silica; Ethyl acetate / water / isopropanol / 0.88 ammonia 25: 8: 15: 2; Rf 0.32.



   Preparation 7: 5- [(4-aminobutoxy) methyl] -N, N-dimethyl-2-furanmethanamine
A mixture of 86 g of methanesulfonic acid, 15.5 g of 5- [(dimethylamino) methyl] -2-furanmethanol and 17.8 g of 4-aminobutanol in dry tetrahydrofuran was heated to 100 ° C. for 1 1/2 hours. Excess sodium carbonate was added to the cooled solution, the suspension was filtered and the filtrate evaporated to give a red oil which was dissolved in water and extracted with ether. The extract was distilled to give 6.6 g of the compound mentioned in the title as an oil, bp 100 to 110 ° C./10.64 Pa. TLC silica; Methanol / O, 88 ammonia 80: 1; Rf 0.3.



   Preparation 8: 2- [3- (4-formylphenoxy) propyl] -1H-isoindole-1,3-dione
24.4 g of 4-hydroxybenzaldehyde and 4.8 g of sodium hydride in 400 ml of dry dimethylformamide were stirred at room temperature for 3 h. 55.0 g of N- (3-bromopropyl) phthalimide were added and the reaction mixture was stirred for a further 5 h. The mixture was poured onto ice and the white solid obtained was recrystallized from a mixture of dichloromethane and cyclohexane, giving 42.4 g of the compound mentioned in the title, mp. 120 to 121 C. TLC silica; Ethyl acetate; Rf 0.7.
 EMI10.2
 heated to give a red oil which was dissolved in acetone and treated with 1.7 g of methyl iodide at room temperature.

   After 2 h the solvent was removed to give 5.58 g of the compound mentioned in the title as a white solid which was washed with ether
 EMI10.3
 ; thylbenzolmethaniumj odid
1.9 g of methyl iodide and 3.9 g of 1-methyl-N5- [3- {3 - [(dimethylamino) methyl] phenoxy} propyl] - - lH-1,2,4-triazole-3,5 diamine in acetonitrile was stirred for 45 min at room temperature. The suspension was heated to 100 ° C. for 15 minutes, giving 4.6 g of the compound mentioned in the title as a yellow solid which was collected and washed with acetonitrile, mp 178 to 179 ° C.



   Preparation 11: Following the procedure of Preparation 5, (i) 10g A and 6.54g 4-hydroxypiperidine 3.6g gave 3- (3- [1- (4-hydroxypiperidinyl) methyl] - - phenoxy} propanamine , Bp 180 C / 13, 3 Pa. TLC silica; ethyl acetate / water / isopropanol / 0.88 ammonia 25: 8: 15: 2; Rf 0.2:

  <Desc / Clms Page number 11>

 
 EMI11.1
 
A solution of 3 g of aminopropanol and 9.8 g of N-cyano-1-methyl-2- (phenylmethylene) hydrazine carboximidothioic acid methyl ester in 50 ml of acetone was heated under reflux for 6 hours.

   The reaction mixture was cooled and the precipitate formed was filtered off and recrystallized from ethyl acetate to give 3.9 g of the compound mentioned in the title as a white solid, mp. 126 to 127 C; TLC silica; Ethyl acetate; Rf 0.35.



    1-methyl-N- (3-hydroxypropyl) -1H-1,2,4-triazole-3,5-diamine
A solution of 3.9 g of N'-cyano-N- [1- (3-hydroxypropyl] -N "- [(phenylmethylene) amino] -N" - - methylguanidine and 20 ml of 2N hydrochloric acid in 100 ml of acetone was added Stirred at 25 C for 18 h.



  Sodium carbonate was added and the solvent removed in vacuo. The residue was crystallized from acetonitrile, giving 2.2 g of the compound mentioned in the title as a white solid, mp. 139 to 140 C. TLC silica; Ethyl acetate / isopropanol / water / 0.88 ammonia 25: 8: 15: 2; Rf 0.5.



   Example 1: (i) 1-Methyl-N3-phenylmethylene-N3- [3- {3 - [(dimethylamino) methyl] phenoxy} propyl] -1H- - 1, 2, 4-triazole-3, 5 diamine
A mixture of 6.08 g of 1-methyl-N3- [3- {3 - [(dimethylamino) methyl] phenoxy} propyl] -1H- - 1, 2, 4-triazole-3, 5-diamine and 2.4 g of benzaldehyde in dry benzene was heated under reflux in a Dean-Stark device for 12 h. The solvent was removed and the residue was purified by column chromatography on silica using methanol to give 7.4 g of the title compound as a yellow oil.

   TLC silica; Methanol / ammonia 80: 1; Rf 0.43.
 EMI11.2
 and 1-methyl [3- {3 - [(dimethylamino) methyl] phenoxy} propyl] -1H-1,2,4-triazole-3,5-diamine (A): (ii) 0, 4 g of 3-pyridinecarboxaldehyde and 1.0 g of A gave 1.23 g of 1-methyl-N3- (3-pyridinylmethylene) [3- {3 - [(dimethylamino) methyl] phenoxy} propyl] -1H- 1,2,4-triazole-3,5-diamine,
Mp 92-93 C. TLC silica; Methanol / ammonia 80: 1; Rf 0.4.



   (iii) 0.4 g of 4-pyridinecarboxaldehyde and 1.0 g of A gave 1.12 g of 1-methyl-N3- (4-pyridinylmethylene) [3- {3 - [(dimethylamino) methyl] phenoxy} propyl] -1H-1,2,4-triazole-3,5-diamine,
Mp 127-128 C. TLC silica; Methanol / ammonia 80: 1; Rf 0.4.



   Example 2: (i) 1-Methyl-N3-phenylmethyl-N5- [3- {3 - [(dimethylamino) methyl] phenoxy) propyl] -1H-1,2,4- - triazole-3,5 diamine
A mixture of 2.0 g of 1-methyl-N3-phenylmethyl-N5- [3- {3 - [(dimethylamino) methyl] - phenoxy) propyl] -1H-1,2,4-triazole-3, 5-diamine and 0.95 g of sodium borohydride in methanol were stirred at 25 C for 12 h. The mixture was poured onto water and extracted with ethyl acetate.



  The organic extract was washed with brine and distilled, giving 1.4 g of the compound mentioned in the title as a pale yellow oil, bp 180 C / 5.32 Pa. TLC silica; Methanol / ammonia 80: 1; Rf 0.7.



   The following compounds were prepared in a similar manner from the corresponding imine and sodium borohydride: (ii) 0.56 g of the 3-pyridinylimine of Example 1 (ii) and 0.075 g of sodium borohydride gave 0.43 g of 1-methyl-N3 - (3-phenylmethyl) -N5- [3- {3 - [(dimethylamino) methyl] phenoxy-propyl-1H-1,2,4-triazole-3,5-diamine. TLC silica; Methanol / ammonia (80: 1);
Rf 0.4.

  <Desc / Clms Page number 12>

 
 EMI12.1
 (6H), 7, 6-8, 2 m (2H).



   (iii) 0.5 g of the 4-pyridinylimine from Example 1 (iii) and 0.075 g of sodium borohydride gave 0.4 g of 1-methyl-N3- (4-pyridinylmethyl) -NI- [3- (3- [(dimethylamino) -methyll-phenoxyl--propyl] -lH-1, 2, 4-triazol-3, 5-diamine, mp. 110 to 111 C. TLC silica; methanol / ammonia 80: 1; Rf 0 , 4th



   Example 3: l-methyl-N'- [3- {3- [(dimethylamino) methyl] phenylamino} propyl) -1H-1,2,4-triazole- 3,5-diamine 3- [( 3-aminopropyl) amino] -N, N-dimethylbenzamide
A mixture of 15.4 g of 3-amino-N, N-dimethylbenzamide and 12 g of N- (3-bromopropyl) phthalimide in dry xylene was refluxed for 12 hours. The precipitate formed was dissolved in methanol and ethyl acetate was added. The mixture was washed with water and the organic phase evaporated to give 15 g of a crude oil which was used without further purification.



   The oil and hydrazine hydrate (5.55 g) were refluxed in ethanol for 2 hours and then cooled to 25 ° C. The solid precipitate formed was filtered off and the filtrate was concentrated in vacuo to give 2.2 g of the compound mentioned in the title, b.p. 170 to 175 C / 1.33 Pa. TLC silica; Methanol / ammonia 80: 1; Rf 0.2.
 EMI12.2
 Pressure of 1862 Pa heated to 100 C for 4 h. The cooled reaction mixture was dissolved in acetone, treated with 2 ml of 1N hydrochloric acid and heated to 60 C for 1/2 h. The mixture was cooled, basified with potassium carbonate and extracted with ethyl acetate.

   Evaporation of the organic extracts gave a viscous oil which was ground with ether; 0.49 g of the compound mentioned in the title were obtained. TLC silica; Methanol / ammonia 80: 1; Rf 0.63.
 EMI12.3
 
A mixture of 0.47 g of 3 - [{3 - [(amino-1-methyl-1H-1,2,4-triazol-5-yl) -amino] -propyl} - - amino] -dimethylbenzamide and 0, 15 g of lithium aluminum hydride in dry tetrahydrofuran was stirred at 25 C for 12 h. Water was added and the reaction mixture was filtered.

   The filtrate was evaporated and the residue was purified by column chromatography on silica using methanol to give 0.07 g of the compound mentioned in the title as a brown solid, mp 101-102 C. TLC silica; Methanol / ammonia 80: 1; Rf 0.53.



   Example 4: 1-Methyl-N5- [3- {3- [1- (1,2,3,6-tetrahydropyridinyl] methyl] phenoxy} propyl] -1H- - 1, 2, 4-triazole- 3, 5-diamine
A solution of 2.62 g of N'-cyano-N- {3- [3- (1,3-dioxolan-2-yl) phenoxy] propyl} -l-methyl-
 EMI12.4
 treated and stirred for a further hour at room temperature. The mixture was treated with 1.5 g of sodium borohydride, stirred at room temperature for 18 h, diluted with ethyl acetate, filtered and the filtrate evaporated in vacuo. The oil obtained was partitioned between ethyl acetate and water. The organic phase was evaporated in vacuo and the residue was purified by column chromatography on silica using methanol.

   Evaporation of the eluates gave the compound mentioned in the title, which consists of a mixture of benzene and
 EMI12.5
 

  <Desc / Clms Page number 13>

 
 EMI13.1
 
1, 26soleic acid; Methanol / ammonia 80: 1; Rf 0.7.



  (iv) 3, 12 g of A and 10 g of heptamethyleneimine gave 0.63 g of 1-methyl-N3- [3- {3 - [(1-heptamethyleneniminyl) methyl] phenoxy} propyl] -1H-1 , 2,4-triazole-3,5-diamine, mp 71-73 C. TLC
Silica; Methanol / ammonia 80: 1; Rf 0.6.



  (v) 1, 74 g A and 10 ml allylamine gave 0.47 g 1-methyl-N5- [3- {3 - [(2-propen-1-amino) - -methyl] -phenoxy} -propyl] - 1H-1,2,4-triazole-3,5-diamine, mp. 71 to 72 C. TLC silica; Methanol / ammonia 80: 1; Rf 0.06



  (vi) 2.42 g of A and 10 ml of benzylamine gave 1.44 g of l-methyl-N "- (3- [3- {[(phenylmethyl) -
 EMI13.2
 
2,4-triazole-3,5-diamine, (vii) 3,43 g A and 10 ml n-propylamine gave 0.2 g 1-methyl-N5- [3- {3 - [(1-propylamino) - -methyl] -phenoxy} -propyl] -1H-1,2,4-triazole-3,5-diamine, mp. 79 to 81 C. TLC silica
 EMI13.3
 ; Ethyl acetate / isopropanol / water / ammonia 25: 15: 8: 2; Rf 0, 7.25: 8: 15: 2; Rf 0.3.



  (xi) 1.98 g and 15 ml of heptylamine gave 0.11 g of 1-methyl-N5 [3- {3- [(heptylamino) methyl] - -phenoxy} -ropyl] -1H-1,2,4- triazole-3,5-diamine, mp 64-65 C. TLC silica;
 EMI13.4
 
TLC silica; Ethyl acetate / water / isopropanol / 0.88 ammonia 25: 8: 15: 2; Rf 0.58.



   (xiv) 4.4 g of A and 20 ml of n-butylamine gave 0.3 g of 1-methyl-N5- [3- {3 - [(butylamino) -methy] - -phenoxy} -propyl] -1H-1, 2,4-triazole-3,5-diamine, mp 99.5 to 101OC. TLC silica; Ethyl acetate / water / isopropanol / 0.88 ammonia 25: 8: 15: 2; Rf 0.45.



   Example 5: (i) 1-methyl-N3-diethyl-N5- [3- {3 - [(dimethylamino) methyl] phenoxy} propyl] -1H-1,2,4-triazole -3,5 diamine
1.0 g of 1-methyl [3- {3 - [(dimethylamino) methyl] phenoxy} propyl] -1H-1,2,4-triazole-3, 5-diamine and 10 ml of acetaldehyde were at room temperature and Atmospheric pressure in ethanol hydrogenated over 10% palladium on activated carbon. The catalyst was filtered off and the filtrate was distilled to give 0.95 g of product as a pale yellow oil, bp 190 C / 7.98 Pa. TLC silica; Methanol: 0.88 ammonia 80: 1; Rf 0.58.



   Similarly, 0.5 g became 1-methyl-N5- [3- {3 - [(dimethylamino) methyl] phenoxy} propyl] - - 1H-1, 2, 4-triazole-3, 5-diamine and 3 ml of propionaldehyde 0.5 g of l-methyl-N3-dipropyl-N5- [3- (3- [(dimethylamino) methyl] phenoxy} propyl] -1H-1,2,4-triazole-3,5 -diamin produced, bp 200 C / 7, 98 Pa.



  TLC silica; Methanol / 0.88 ammonia 80: 1; Rf 0.53.

  <Desc / Clms Page number 14>

 
 EMI14.1
 The pyridine was removed and the residue was dissolved in ethyl acetate. The organic solution was washed with aqueous sodium carbonate and evaporated to give 1.1 g of the compound mentioned in the title as a pale yellow oil. TLC silica; Methanol / 0.88 ammonia 80: 1; Rf 0.49.
 EMI14.2
 
1, 42-3, 5-diamine
A mixture of 1.1 g of N- {5- ([3- {3- [(dimethylamino) methyl] phenoxy} propyl] amino) - - 1-methyl-1H-1,2,4-triazole -3-yl} -acetamide, 0.15 g of lithium aluminum hydride and 20 ml of tetrahydrofuran was refluxed for 12 hours under a nitrogen atmosphere.

   The mixture was quenched with 5 ml of water, filtered and the filtrate was distilled, giving 0.6 g of the compound mentioned in the title as a pale yellow oil, bp. 220 ° C./7.98 Pa. TLC Kieseläusre; Methanol / 0.88 ammonia 80: 1; Rf 0, 54.
 EMI14.3
 : 1-Methyl-N3-methyl-N5 - [3- {3- [(dimethylamino) -methyl] -phenoxy} -propyl] -lH-1, 2, 4-- 3, 5-diamine
A mixture of 0.35 g of 5- ([3- {3- [(dimethylamino) methyl] phenoxy} propyl] amino) -l-methyl-1H-1,2,4-triazole-3 -carbamic acid ethyl ester, 0.13 g of lithium aluminum hydride and 10 ml of tetrahydrofuran was refluxed for 48 hours. The mixture was quenched with 0.5 ml of water, filtered and the filtrate evaporated.

   The residue was purified by column chromatography on silica using methanol as the eluent to give 0.1 g of the title compound as a pale yellow oil. TLC silica; Methanol / 0.88 ammonia 80: 1; Rf 0.43.
 EMI14.4
    2,78azole-3,5-diamine in 85 ml of ethyl acetate was added to a solution of 5.9 g of succinic acid in 80 ml of boiling ethanol. The mixture was cooled, stirred at room temperature for 1 h and filtered, giving 33.1 g of the compound mentioned in the title as a white crystalline solid, mp. 118 to 121 C. UV data: EI in water at 267 nm = 46. 2nd



   Example 9: 1-Methyl-N3- (5-hydroxypentyl) -N5- [3- {3 - [(dimethylamino) methyl] phenoxy} propyl- - lH-1, 2, 4-triazole-3, 5 diamine
1.0 g of l-methyl-N "- [3- {3 - [(dimethylamino) methyl] phenoxy} propyl] -1H-1,2,4-triazole-3,5-diamine and 1.9 ml of 5-hydroxypentanal was refluxed for 5 hours in 30 ml of ethanol, the solution was cooled to 5 ° C. and treated with 0.76 g of sodium borohydride.

  <Desc / Clms Page number 15>

 Pension was stirred for 16 h at room temperature, treated with water and concentrated in vacuo. The aqueous solution was extracted with ethyl acetate and the organic extracts were distilled to give 0.47 g of the compound mentioned in the title as a pale yellow oil, b.p.



    250 C / 66.5 Pa. TLC silica; Ethyl acetate / isopropanol / water / 0.88 ammonia 25: 15: 8: 2; Rf 0.6.



   Example 10: According to the procedure of Example 4, (i) from 1.92 g A and 10 ml 0.88 ammonia 0.15 g 1-methyl-N5 - {3- [3- (aminomethyl) -phen-
 EMI15.1
 amine 1-methyl-N'- (3- [3- (1,3-dioxolan-2-yl) phenoxyl-propyl-1H-1,2,4-triazole-3,5-diamine
A solution of 2.50 g of N'-cyano-N- {[3- (1,3-dioxolan-2-yl) phenoxy] propyl} -l-methyl- - 2-phenylmethylene hydrazine carbo, imidamide in 6 ml of piperidine was heated to reflux for 70 h. The mixture was evaporated in vacuo and the oil obtained was chromatographed on silica.

   Elution with a mixture of methanol and ethyl acetate (1: 1) gave an oil which was crystallized from a mixture of benzene and cyclohexane to give 0.29 g of the compound mentioned in the title, mp 117 to 118 C. TLC silica (methanol), Rf 0.7.
 EMI15.2
    [3- (1-piperidinylmethyl) phenoxy] propyl-1H-1,2,3-triazole-3,5-diaminazole-3,5-diamine in 2 ml tetrahydrofuran was mixed with 0.2 ml 2N hydrochloric acid 1 / Stirred for 2 h at room temperature. The mixture was treated with 0.5 ml of piperidine, stirred at room temperature for 1 h and then treated with 75 mg of sodium borohydride. After a further hour the mixture was diluted with water and extracted with ethyl acetate. The combined extracts were dried and evaporated in vacuo.

   The oil obtained was crystallized from a mixture of benzene and cyclohexane to give 60 mg of the compound mentioned in the title, mp. 93 to 94 C. TLC silica; Methanol / ammonia 80: 1; Rf 0.5.
 EMI 15.3
 :? - {4- [3- (1-Piperidinylmethyl) phenoxy] butyl} -1H-1,2,4-triazole-3,5-diamine11.2 g of 3- (1-piperidinylmethyl) phenol were added added to a stirred suspension of 1.5 g of sodium hydride in 60 ml of dimethylformamide at room temperature. The mixture was stirred at room temperature for 5 hours and treated with 9 g of 4-bromobutanenitrile. After a further 24 h at room temperature the mixture was poured onto ice and extracted with ethyl acetate. The combined extracts were washed with water and evaporated in vacuo.

   The remaining oil was distilled under reduced pressure to give 14.8 g of the compound mentioned in the title, bp 200 ° C./7.98 Pa. TLC silica; Methanol / ammonia 80: 1; Rf 0.8.



   4- [3- (1-piperidinylmethyl) phenoxy] butanal semicarbazone
A solution of 5.16 g of 4- [3- (1-piperidinylmethyl) phenoxy] butanenitrile, 7.38 g of sodium acetate and 7.76 g of semicarbazide hydrochloride in 60 ml of ethanol and 60 ml of water was added over 12 g of Raney nickel Room temperature and about 1 bar hydrogenated. The mixture was filtered and concentrated to 50 ml in vacuo. The resulting solution was diluted with water, made basic with potassium carbonate and extracted with ethyl acetate. The organic extracts were evaporated to give an oil which was chromatographed on silica with methanol as the eluent; 4.4 g of the compound mentioned in the title were obtained as a colorless oil.



  TLC silica; Methanol / ammonia 80: 1; Rf 0.7.

  <Desc / Clms Page number 16>

 



   NMR (CDCIa): 0, 28 broad s (1H), 2, 6-2, 9 m (2H), 3, 0-3, 4 m (3H), 4, 4 broad s (2H), 6, 02 t (2H), 6.57 s (2H), 7.4-8.9 m (14H).



    4- [3- (1-piperidinylmethyl) phenoxy] butanal
A solution of 4.34 g of 4- [3- (1-piperidinylmethyl) phenoxy] butanal semicarbazone in 40 ml of 2N hydrochloric acid was stirred with 40 ml of 37% strength aqueous formaldehyde solution for 1 hour at room temperature. The mixture was diluted with water, treated with potassium carbonate and extracted with ethyl acetate. The combined organic extracts were evaporated in vacuo and the remaining oil was chromatographed on silica with methanol as the eluent, 1.93 g of the compound mentioned in the title being obtained as a colorless oil. TLC silica; Methanol; Rf 0.5.
 EMI16.1
    : 0.1 amino-1,2,4-triazole in 20 ml abs. Ethanol was refluxed for 2 hours.

   The cooled solution was treated with 200 g of sodium borohydride and stirred at room temperature for 18 hours. The mixture was evaporated in vacuo and the residue was partitioned between ethyl acetate and water. The combined organic extracts were evaporated in vacuo and the residue was chromatographed on silica with methanol as the eluent, giving 250 mg of the compound mentioned in the title as an oil. TLC silica; Ethyl acetate / isopropanol / water / ammonia 25: 15: 8: 2; Rf 0.4.
 EMI16.2
   : 2,8-lH-1,2,4-triazole-3,5-diamine
2.39 g of 1-methyl-N3- {3- [3- (1-piperidinylmethyl) phenoxy] propyl} -1H-1,2,4-triazole-3,5-diamine and 2.96 g of methoxyacetaldehyde were added heated in reflux in 50 ml of ethanol and 10 ml of 2N hydrochloric acid for 24 h.



   The cooled reaction mixture was treated with 7.6 g of sodium borohydride and stirred for 24 hours at room temperature. The suspension was treated with water, filtered and the filtrate extracted with ethyl acetate. The organic extracts were distilled to give 0.2 g of the compound mentioned in the title as a yellow oil, b.p. 250 C / 7.98 Pa. TLC silica; Ethyl acetate / isopropanol / water / 0.88 ammonia 25: 15: 8: 2; Rf 0.65.

** WARNING ** End of DESC field may overlap beginning of CLMS **.

 

Claims (1)

 PATENT CLAIMS: 1. Process for the preparation of new 1, 2, 4-triazole derivatives of the general formula  EMI 16.3  wherein Rl and R: are the same or different and each represents hydrogen, C1-10 alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, trifluoroalkyl or alkyl, substituted by hydroxy, alkoxy, amino, alkylamino, dialkylamino or cycloalkyl, or R, and R:    together with the nitrogen atom to which they are attached form a 5- to 10-membered alicyclic heterocyclic ring which may be saturated or contain at least one double bond, unsubstituted or optionally substituted by one or more Cl 3 alkyl groups, such as methyl, or a hydroxy group and / or can contain a further heteroatom, such as oxygen or sulfur; Alk is straight or branched alkylene with 1 to 6 C atoms, preferably 1 to 4 C atoms;  Q represents a furan or thiophene ring, the bond to the molecular residue via the positions  <Desc / Clms Page number 17>    EMI17.1    EMI17.2    EMI17.3    EMI17.4    EMI17.5  represents hydrogen, alkyl, alkenyl, aralkyl, hydroxyalkyl having at least 2 carbon atoms, alkoxyalkyl or aryl;  and R4 and Rs are the same or different and are each hydrogen, alkyl, hydroxy or C1-3 alkoxy substituted alkyl, alkenyl, aralkyl or pyridylalkyl, the pyridyl part  EMI17.6    EMI17.7  may, or R, and Rs together represent the group = CRsRg, in which R9 is aryl or heteroaryl and Re is hydrogen or alkyl, and their physiologically usable salts and hydrates, characterized in that for the preparation of compounds in which R. and Rs are have meaning other than = CH8R9, a compound of the general formula  EMI 17.8    EMI17.9  inducible group, where RCH. has the meaning of R; D '- CH2NH- or -CONH- or -CH = N-, and D''NRRs, where R .. and R s have the meaning given in formula (I) or -NR4COR11, where R4 is that in formula (I) has the meaning given and R "is hydrogen, alkyl, optionally substituted by hydroxy, aryl, aralkyl or alkoxy, where at least one of the groups D, D 'and D" is a reducible group, reduced and if D is CHO , additionally aminated within the stated possibilities, whereupon a compound of the formula (I) in which R4 and Rs are both hydrogen, optionally with the aldehyde or ketone R, to prepare compounds in which R4 and Rs form the group = CReRg, R.) CO, in which R a and Rg have the meaning given in formula (I),  implements; and / or a compound (I) obtained is converted into a salt.  EMI 17.10    EMI17.11    EMI17.12  where the total of m + n is 3 or 4.  4. The method according to claim 3, characterized in that one uses starting compounds, wherein the total sum of m + n is 3.  5. The method according to claim 1, characterized in that one uses starting compounds in which X is sulfur, n is 1 and m is 2.  <Desc / Clms Page number 18>    EMI18.1    EMI18.2    EMI18.3  is, with the binding to the molecular residue via the positions 1 and 3 or 1 and 4.  8. The method according to any one of claims 1 to 7, characterized in that one uses initial changes in which alk is methylene, ethylene or propylene.  9. The method according to any one of claims 1 to 7, characterized in that starting  EMI18.4  mean or R1 and R2 together with the nitrogen atom to which they are attached form an alicyclic heterocyclic ring having 5 to 8 members and optionally have a double bond and / or are substituted by hydroxy or 1 or 2 C 1-3 alkyl groups.  10. The method according to any one of claims 1 to 9, characterized in that starting compounds are used in which R3 is hydrogen, C 1-4 alkyl or hydroxyalkyl.  11. The method according to any one of claims 1 to 10, characterized in that starting compounds are used in which R4 is hydrogen or Cs-alkyl, optionally substituted by phenyl, pyridyl, hydroxy or C1-3alkoxy, and R5 is hydrogen or Cl 3-alkyl or R4 and R5 together with the nitrogen atom to which they are attached form a C, -saturated heterocyclic ring.  12. The method according to any one of claims 1 to 10, characterized in that one  EMI18.5     IR2 NAlk, R 1 and Pu, together with the nitrogen atom to which they are attached, form a heterocyclic ring which may be pyrrolidine, piperidine, optionally substituted in position 4 by C 1-3 alkyl, tetrahydropyridine or hexamethyleneimine.  13. The method according to any one of claims 1 to 12, characterized in that starting compounds are used in which Q is a furan or substituted furan ring, alk  EMI 18.6  and R 2 both represent C1-3 alkyl groups and when R7 represents a C1-3 alkyl group optionally substituted by a C1-3 alkoxy group, n is 1, X is sulfur and m is 2.  14. The method according to any one of claims 1 to 12, characterized in that starting compounds are used in which Q is a benzene ring, alk is a methylene, ethylene  EMI18.7  R2 is a straight chain Cl 7 alkyl group which may be branched by a methyl group or is a C1-4 alkyl group which is substituted by a di (C1-3) alkylamino, C1-3 alkoxy, trifluoromethyl or Phenyl group may be substituted, or R2 is a C5-7 cycloalkyl group or.  , -Alkenyl group or Rl and R2 together with the nitrogen atom to which they are attached form a 5- or 8-membered alicyclic heterocyclic ring which can be saturated and can contain at least one double bond, or saturated and by one or more C1-3 alkyl groups can be substituted and can contain a further heteroatom, R represents hydrogen, C .., - alkyl or hydroxyethyl, R4 is hydrogen or C1-3 alkyl, optionally substituted by a phenyl or pyridyl group, and R5 is hydrogen or Cl-3 -Alkyl means.  15. The method according to claim 1, characterized in that starting compounds  EMI 18.8     R2 NAlk, C 1-6 alkyl substituted by alkoxy, alkylamino or dialkylamino or Rl and R2 together with the nitrogen atom to which they are attached are a 5- to 10-membered alicyclic  <Desc / Clms Page number 19>  form a heterocyclic ring which may contain oxygen; Alk represents a straight-chain or branched-chain alkylene chain with 1 to 6 C atoms;  Q is a furan or thiophene ring, the binding to the molecular residue taking place via positions 2 and 5 and the furan ring optionally  EMI19.1  and R4 and R5 may be the same or different and each represent hydrogen or C. e-alkyl, with the proviso that when Q is a furan, substituted furan or thiophene ring system and X is oxygen, n has a meaning other than zero .  16. The method according to claim 1, characterized in that reacting a compound of formula (I) obtained with an aldehyde of formula R, HCO, wherein Rn is pyridyl or phenyl.  17. The method according to claim 1, characterized in that 1-methyl-NS - {3- [3-1-  EMI19.2